In conjunction with the 2002 Prescription Drug User Fee Act (PDUFA) Reauthorization Performance Goals and Procedures (PDUFA III Goals), the Food and Drug Administration (FDA) agreed to meet specific performance goals to improve the effectiveness and efficiency of FDA review of New Drug Applications (NDAs) and Biologic License Applications (BLAs). Several of these goals are focused on improving the review process activities occurring between initial submission of the application and subsequent FDA action regarding the application (i.e., first-cycle review). The focus of this study is to identify and examine what factors contribute to and detract from FDA’s ability to make an approval decision during the first-cycle review for products that are ultimately approved without major new data submissions. This evaluation contract was to determine the impact of FDA’s initiatives to enhance first-cycle review performance during the five-year period of PDUFA III. The scientific merit of an application, while of critical importance to approval decisions, was not within the scope of this study; nonetheless, a significantly deficient application cannot be expected to attain first-cycle approval, even if the product is ultimately found to be safe and effective.

Booz Allen conducted a two-part study of first-cycle review initiatives: a Retrospective Analysis[1] and a Prospective Analysis. The studies focused on the first-cycle review processes that are conducted on NDAs for new molecular entities (NMEs) and BLAs. The Overall Study Cohort included 185 NME NDAs and BLAs that were received during fiscal years 2002-2007 and reached first action by September 30, 2007. The first-cycle approval rate for the 185 applications was 50%. The FY2002 – FY2007 cohort was comprised of 74% NDAs and 26% BLAs. The NDAs had a 43% first-cycle approval rate, while the BLAs rate was higher for both Center for Drug Evaluation and Research (CDER) (86%) and Center for Biologics Evaluation and Research (CBER) (66%).

Product and Disease Characteristics

The study examined several product and disease characteristics, including review designation, condition severity and mechanism of action. Priority review designation, which is given to applications for products that offer major advances in treatment or provide a treatment where no adequate therapy exists, had the most significant impact on first-cycle approval rates. Within this FY2002 – FY2007 cohort, 45% had Priority designation. Applications with a Priority designation had a higher first-cycle approval rate (68%) than products with Standard review designation (36%) (Note that Priority reviews have a six month goal for initial action, while Standard reviews have a ten month goal for initial action). Booz Allen speculates that this higher first-cycle approval rate for Priority approval drugs reflects a greater effort to resolve issues during the first cycle, which is consistent with FDA’s commitment to provide access to therapies for unmet medical needs. Products with a novel mechanism of action (MOA) targeting life-threatening conditions had a greater first-cycle approval rate (62%) compared to that of products with non-novel MOAs addressing non-life-threatening conditions (39%).

Good Review Management Principles and Practices Compliance

We observed that applications that complied with most or all of the assessed Good Review Management Principles and Practices (GRMPs) activities had the highest first-cycle approval rates. For applications assessed after the FY2005 GRMPs rollout, application reviews that complied with 80% of assessed GRMPs activities and timeframes [2] or more had a first-cycle approval rate of 71% compared to the first-cycle approval rate of 50% for those application reviews that complied with 20% of GRMPs assessed activities. In conducting a closer examination of the assessed GRMPs activities and timeframes, there was no single factor that contributed to the higher first-cycle approval rate.

Issue Identification

The resolution of major application issues was critical to first-cycle approval. In many instances issues identified early in the review process by FDA were not addressed by the sponsor in a timely manner or were not resolved during the first cycle. Applications with major deficiencies identified and documented by FDA either pre-submission or during the review were less likely to be approved in a single cycle than those applications that did not have a major deficiency identified during the same timeframe. However, applications were more likely to be approved in the first cycle if a major deficiency was identified pre-submission (40%) than if major deficiencies were identified during the review (19%). Applications for which no major deficiency was identified either pre-submission or during the review had a high first-cycle approval rate (92%). The majority of multi-cycle applications have major deficiencies in one or two key categories; these were in the critical areas of safety, efficacy or chemistry manufacturing and controls (CMC).

Communication Characteristics

Sponsors continue to take advantage of the pre-submission meeting opportunities: End of Phase 2 (EOP2) and Pre-NDA/BLA. There was a significant increase in the number of applications that had an EOP2 and/or Pre-NDA/BLA meeting from FY2002 to FY2007. In the Prospective Analysis Cohort, 78% of sponsors participated in EOP2 meetings and 93% participated in Pre-NDA/BLA meetings. In addition, sponsors who submitted their application to FDA within six months of the Pre-NDA/BLA meeting had a 71% first-cycle approval rate, as compared to a 39% first-cycle approval rate for those that submitted their application more than six months from the date of the meeting.

The Filing Review Notification, or 74-Day Letter, is an effective tool in communicating deficiencies to sponsors. For applications submitted FY2005 – FY2007, 62% of these applications had all potential review issues [3] that were listed in the 74-Day Letter resolved by the action date. Of those that resolved the potential review issues conveyed in the letter, 62% were approved in the first cycle, indicating that FDA successfully identified and communicated important review issues to the sponsor in the Filing Review Notification.

Throughout the review cycle, the FDA and sponsors frequently engage in informal communications (email, telephone, and fax) in addition to face-to-face meetings. Analysis of Action Packages [4] and FDA systems demonstrated that the frequency of FDA-sponsor communications was similar for single-cycle and multi-cycle reviews for the first three-quarters of the application review cycle. In the final quarter of the review cycle, however there was a significant increase in communications for single cycle approvals compared to multiple cycle applications. Approximately 70% of these additional communications were related to labeling and postmarketing study commitments (PMC) issues, which is not surprising since these communications are needed in the final stages of an approval action.

Recommendation:
Booz Allen recommends a continued shift in emphasis of discussing data in addition to application format issues in key pre-submission meetings so as to promote earlier issue identification and resolution. Booz Allen also recommends that FDA should continue to use the 74-Day Letter to communicate application deficiencies early in the review process. To improve the efficiency and the effectiveness of the review process, Booz Allen recommends that FDA and sponsors agree on an application review communication protocol during filing determination, which would set expectations for sponsors about appropriate methods (e.g., secure email) and timeframes for FDA communication.

Sponsor Characteristics

Sponsor size was a contributing factor to first-cycle approval rates, with large companies receiving first-cycle approval 58% of the time, compared to only 41% for small companies. Large companies were more likely to have prior FDA experience than small companies, a factor which is also correlated with higher first-cycle approval rates. These larger, more experienced companies often took advantage of opportunities to discuss product development issues in pre-submission meetings than smaller companies. Further, large companies on average had more communications with FDA throughout the application review cycle than smaller companies, which may have helped them to more rapidly identify and address potential review issues. Even for multi-cycle applications, smaller sponsors tended to have deficiencies covering a wider spectrum included in the action letter compared to larger sponsors, further suggesting that larger companies have fewer review issues and are able to leverage their experience and resources to identify and resolve issues in a timely manner. Booz Allen speculates inexperienced sponsors would probably benefit from additional FDA-initiated efforts to clarify review processes and guidances on product development.

Recommendation:
Booz Allen recommends that sponsors should maximize the efficiency and the effectiveness of the review process by tracking and resolving the issues identified during pre-submission meetings (e.g., EOP2, Pre-NDA/BLA), and actively resolving those issues identified during the review phase to the extent practicable.

FDA Characteristics

The FDA received a significantly higher number of NDAs for NMEs and BLA submissions in the fourth quarter (44% of annual total) compared to any other quarter in the calendar year (19% of total per quarter, on average). These applications had the lowest rate of first-cycle approvals. Examination of other factors (e.g., review designation, sponsor size, sponsor experience) did not provide any insight regarding the significant differences with these applications in comparison to applications submitted in other quarters. Booz Allen speculates that application quality may contribute to the lower first-cycle approval rate of fourth quarter submissions; however, the quality of an application was not within the scope of this study.